3,6-substituted imidazol[1,2-b]pyridazine analogs for treating allergic and inflammatory diseases

ABSTRACT

Methods for treating an allergic or inflammatory disease or other Syk-mediated disease or Syk-mediated condition characterized by administering a composition which contains a therapeutically effective amount of a 3,6-substituted imidazol[1,2-b]pyridazine compound.

This application claims priority to U.S. Provisional Applications, U.S.Ser. Nos. 60/643,386 filed Jan. 12, 2005, and 60/695,967 filed Jul. 1,2005.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the treatment of allergic orinflammatory diseases or other Syk-mediated diseases or conditions. Moreparticularly, the present invention relates to the topical or systemicadministration of certain 3,6-substituted imidazol[1,2-b]pyridazineanalogs for the treatment of such diseases or conditions.

2. Description of the Related Art

Syk is a tyrosine kinase that plays a critical role in mast celldegranulation, eosiniphil activation, lipid mediator synthesis andcytokine production. Accordingly, Syk kinase is implicated in variousinflammatory and allergic disorders in particular asthma.

It has been shown that Syk binds to the phosphorylated gamma chain ofthe high affinity IgE receptor (Fcε RI) signaling via N-terminal SH2domains and is essential for downstream signaling [Taylor et al,Molecular and Cellular Biology 1995; 15:4149-4157]. Syk kinase isimportant in the intracellular propagation of signaling following thecrosslinking of the high affinity IgG receptor (FcγRI) by IgG. Since themediators released as the results of Fcε RI and FcγRI are responsible atleast in part for adverse effects associated with allergic responses orinflammation, compounds that inhibit Syk kinase may be effective ininhibiting those adverse effects [Sirganian et. al. Molecular Immunology2002, 38:1229-1233].

The term “Syk-mediated disease” or “Syk-mediated condition”, as usedherein, means any disease or other deleterious condition in which Sykprotein kinase is known to play a role. Such conditions include, withoutlimitation, inflammation and allergic disorders, especially asthma.

As taught in WO 2004/014382 (Rigel Pharmaceuticals) certain2,4-pyridinediamine compounds have Syk kinase inhibitory activity. Laiet. al. describe a series of oxindoles having Syk kinase activity[Biorganic and Medicinal Chemistry Letters 2003, 13:3111-3114. Cywin et.al. describe the activity of a series of [1,6]naphthyridine compoundsthat inhibit Syk kinase [Biorganic and Medicinal Chemistry Letters 2003,13:1415-1418]. Yamamoto et. al. describe an orally availableimidazo[1,2,c]pyrimidine Syk kinase inhibitor [Journal of Pharmacologyand Experimental Theapeutics 2003, 306:1174-1181]. WO2004/085409discloses 5-substituted 2,3-diaminopyrazines.

SUMMARY OF THE INVENTION

The present invention provides a method for treating an allergic orinflammatory disease or other Syk-mediated disease or Syk-mediatedcondition characterized by administering a formulation which contains atherapeutically effective amount of a 3,6-substitutedimidazol[1,2-b]pyridazine compound of formula (I) or a pharmaceuticallyacceptable salt thereof. The compounds of formula (I) have Syk kinaseinhibitory activity. In one embodiment, the compounds of formula (I) areadministered topically to treat an allergic or inflammatory disease orother Syk-mediated disease or Syk-mediated condition of the eye, ear ornose. In a preferred embodiment, the compounds of the present inventionare used to treat an allergic eye disease selected from the groupconsisting of allergic conjunctivitis; vernal conjunctivitis; vernalkeratoconjunctivitis; and giant papillary conjunctivitis.

DETAILED DESCRIPTION OF THE INVENTION

The 3,6-substituted imidazol[1,2-b]pyridazine compounds useful in themethods of the present invention are defined by formula (I):

wherein:A=aryl or heteroaryl optionally substituted by F, Cl, Br, C₁-C₆ alkyl,OR², or OCF₃;R¹═H, C₁-C₆ alkyl, heterocyclyl, or (CH₂)_(n)—X;n=1-4;X=aryl, heteroaryl, OR⁵ or NR³R⁴; andR², R³, R⁴, R⁵ independently=H or C₁-C₆ alkyl.

According to a preferred embodiment of the present invention, a compoundof formula (I), or a pharmaceutically acceptable salt thereof, istopically administered to the eye. Examples of pharmaceuticallyacceptable salts of the compounds of formulas (I) include, but are notlimited to, inorganic acid salts such as hydrochloride, hydrobromide,sulfate and phosphate; organic acid salts such as acetate, maleate,fumarate, tartrate and citrate; alkali metal salts such as sodium saltand potassium salt; alkaline earth metal salts such as magnesium saltand calcium salt; metal salts such as aluminum salt and zinc salt; andorganic amine addition salts such as triethylamine addition salt (alsoknown as tromethamine), morpholine addition salt and piperidine additionsalt.

It is recognized that compounds of Formula (I) can contain one or morechiral centers. This invention contemplates all enantiomers,diastereomers, and mixtures thereof. In the above definitions, the totalnumber of carbon atoms in a substituent group is indicated by theC_(i)-C_(j) prefix, where the numbers i and j define the number ofcarbon atoms; this definition includes straight chain, branched chain,and cyclic alkyl or (cyclic alkyl)alkyl groups.

The term “aryl” refers to a monocyclic, bicyclic or tricyclic ringsystem having a total of five to fourteen ring members, wherein at leastone ring in the system is aromatic and wherein each ring in the systemcontains 3 to 7 ring members. The term “aryl” may be usedinterchangeably with the term “aryl ring”.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used hereinmeans non-aromatic, monocyclic, bicyclic or tricyclic ring systemshaving three to fourteen ring members in which one or more ring membersis a heteroatom, wherein each ring in the system contains 3 to 7 ringmembers.

The term “heteroaryl” refers to monocyclic, bicyclic or tricyclic ringsystems having three to fourteen ring members wherein at least one ringin the system is aromatic, at least one ring in the system contains oneor more heteroatoms, and wherein each ring in the system contains 3 to 7ring members.

The term “heteroatom” means nitrogen, oxygen, or sulfur and includes anyoxidized form of nitrogen and sulfur, and the quarternized form of anybasic nitrogen. Also the term “nitrogen” includes a substitutablenitrogen of a heterocyclic ring. As an example, in a saturated orpartially unsaturated ring having 0-3 heteroatoms selected form oxygen,sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as insubstituted pyrrolidinyl).

It is important to recognize that a substituent may be present eithersingly or multiply when incorporated into the indicated structural unit.

The compounds of this invention are commercially available (BioFocusDiscovery, Ltd., United Kingdom).

The compounds of the present invention may be administered topically(i.e., local, organ-specific delivery) by means of conventional topicalformulations, such as solutions, suspensions or gels for the eye andear; nasal sprays or mists for the nose. The concentration of the3,6-substituted imidazol[1,2-b]pyridazine compound of formula (I) in theformulations of the present invention will depend on the selected routeof administration and dosage form, but will generally range from 0.00001to 5% (w/v). For solutions intended for topical administration to theeye, the concentration of the 3,6-substituted imidazol[1,2-b]pyridazinecompounds of formulas (I) is preferably 0.0001 to 0.5% (w/v). Thetopical compositions of the present invention are prepared according toconventional techniques and contain conventional excipients in additionto one or more 3,6-substituted imidazol[1,2-b]pyridazine compounds offormula (I). A general method of preparing eye drop compositions isdescribed below:

One or more 3,6-substituted imidazol[1,2-b]pyridazine compounds offormula (I) and a tonicity-adjusting agent are added to sterilizedpurified water and if desired or required, one or more excipients. Thetonicity-adjusting agent is present in an amount sufficient to cause thefinal composition to have an ophthalmically acceptable osmolality(generally about 150-450 mOsm, preferably 250-350 mOsm). Conventionalexcipients include preservatives, buffering agents, chelating agents orstabilizers, viscosity-enhancing agents and others. The choseningredients are mixed until homogeneous. After the solution is mixed, pHis adjusted (typically with NaOH or HCl) to be within a range suitablefor topical ophthalmic use, preferably within the range of 4.5 to 8.

Many ophthalmically acceptable excipients are known, including, forexample, sodium chloride, mannitol, glycerin or the like as atonicity-adjusting agent; benzalkonium chloride, polyquaternium-1 or thelike as a preservative; sodium hydrogenphosphate, sodiumdihydrogenphosphate, boric acid or the like as a buffering agent;edetate disodium or the like as a chelating agent or stabilizer;polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid,polysaccharide or the like as a viscosity-enhancing agent; and sodiumhydroxide, hydrochloric acid or the like as a pH controller.

According to the present invention, the 3,6-substitutedimidazol[1,2-b]pyridazine compounds of formulas (I) are useful fortreating an allergic or inflammatory disease or other Syk-mediateddiseases or Syk-mediated conditions. Such disorders include, but are notlimited to, septic shock, haemodynamic shock, sepsis syndrome, postischaemic reperfusion injury, malaria, mycobacterial infection,meningitis, psoriasis, congestive heart failure, fibrotic diseases,cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma,diseases involving angiogenesis, autoimmune diseases, skin inflammatorydiseases, inflammatory bowel diseases such as Crohn's disease andcolitis, osteo and rheumatoid arthritis, ankylosing spondylitis,psoriatic arthritis, adult Still's disease, ureitis, Wegener'sgranulomatosis, Behcet's disease, Sjogren's syndrome, sarcoidosis,polymyositis, dermatomyositis, multiple sclerosis, radiation damage,hyperoxic alveolar injury, periodontal disease, HIV, non-insulindependent diabetes mellitus, systemic lupus erythematosus, glaucoma,sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia,retinal disease, scleroderma, osteoporosis, renal ischemia, myocardialinfarction, cerebral stroke, cerebral ischemia, nephritis, hepatitis,glomerulonephritis, cryptogenic fibrosing aveolitis, transplantrejection, atopic dermatitis, vasculitis, ophthalmic allergic disorders,otic allergic disorders, nasal allergic disorders, rhinitis, sinusitis,reversible airway obstruction, adult respiratory distress syndrome,asthma, chronic obstructive pulmonary disease, and bronchitis.

In a preferred embodiment the compounds of formula (I) are useful intreating ophthalmic allergic disorders, including allergicconjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, andgiant papillary conjunctivitis; nasal allergic disorders, includingallergic rhinitis and sinusitis; and otic allergic disorders, includingeustachian tube itching.

For ocular disorders, the eye drops produced by the above methodtypically need only be applied to the eyes a few times a day in anamount of one to several drops at a time, though in more severe casesthe drops may be applied several times a day. A typical drop is about 30μl.

Certain embodiments of the invention are illustrated in the followingexamples.

Example 1: Topical Ophthalmic Solution Formulation IngredientConcentration (W/V %) Compound of formula I 0.1 Dibasic Sodium Phosphate0.5 (Anhydrous), USP Sodium Chloride, USP 0.65 Benzalkonium Chloride0.01 Sodium Hydroxide, NF q.s. pH 7.0 ± 0.2 Hydrochloric Acid, NF q.s.pH 7.0 ± 0.2 Purified Water q.s. 100

Example 2: Topical Ophthalmic Gel Formulation Ingredient Concentration(W/V %) Compound of formula I 0.1 Carbopol 974 P 0.8 Disodium EDTA 0.01Polysorbate 80 0.05 Benzalkonium Chloride, Solution 0.01 + 5 xs SodiumHydroxide q.s. pH 7.0 ± 0.2 Hydrochloric acid q.s. pH 7.0 ± 0.2 Waterfor Injection q.s. 100

Example 3 Syk Kinase Activity

In a final reaction volume of 25 μl, Syk (h) (5-10 mU) is incubated with50 mM Tris pH 7.5, 0.1 EGTA, 0.1 mM Na₃VO₄, 0.1% β-mercaptoethanol, 0.1mg/mL poly (Glu, Tyr) 4:1, 10 μM test agent, 10 mM MgAcetate and[γ-³³P-ATP] (specific activity approximately 500 cpm/pmol, concentrationas required). The reaction is initiated by the addition of the MgATPmix. After incubation for 40 minutes at room temperature, the reactionis stopped by the addition of 5 μl of a 3% phosphoric acid solution. 10μl of the reaction is then spotted onto a Filtermat A and washed threetimes for 5 minutes in 75 mM phosphoric acid and once in methanol priorto drying and scintillation counting. Percent inhibition was calculatedusing the following formula:% Control=((sample−mean no enzyme)/(mean plus enzyme−mean noenzyme))×100.

In the syk kinase inhibition assay described above, the compounds shownin Table 1 were tested and were found to inhibit syk kinase; the resultsare shown in Table 1 below.

TABLE 1 Structure % inhibition

81

77

42

38

33

27

26

24

23

1. A method for treating an allergic or inflammatory disease or otherSyk-mediated disease or Syk-mediated condition in a patient whichcomprises administering to the patient a composition comprising atherapeutically effective amount of a compound of the formula:

wherein: A=aryl or heteroaryl optionally substituted by F, Cl, Br, C₁-C₆alkyl, OR², or OCF₃; R¹═H, C₁-C₆ alkyl, heterocyclyl, or (CH₂)_(n)—X;n=1-4; X=aryl, heteroaryl, OR⁵ or NR³R⁴; and R², R³, R⁴, R⁵independently=H or C₁-C₆ alkyl; provided that the allergic orinflammatory disease of other Syk-mediated disease or Syk-mediatedcondition is an ophthalmic allergic disorder.
 2. The method of claim 1wherein the composition is topically administered to the patient.
 3. Themethod of claim 2 wherein the therapeutically effective amount of thecompound is 0.00001-5% (w/v).
 4. The method of claim 3 wherein thetherapeutically effective amount of the compound is 0.0001-0.5% (w/v).5. The method of claim 1 wherein the composition is topicallyadministered to the eye of the patient.
 6. The method of claim 1 whereinthe ophthalmic allergic disorder is selected from the group consistingof allergic conjunctivitis; vernal conjunctivitis; vernalkeratoconjunctivitis; and giant papillary conjunctivitis.